Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L31/00—Materials for other surgical articles, e.g. stents, stent-grafts, shunts, surgical drapes, guide wires, materials for adhesion prevention, occluding devices, surgical gloves, tissue fixation devices
  • A61L31/08—Materials for coatings
  • A61L31/10—Macromolecular materials
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61F—FILTERS IMPLANTABLE INTO BLOOD VESSELS; PROSTHESES; DEVICES PROVIDING PATENCY TO, OR PREVENTING COLLAPSING OF, TUBULAR STRUCTURES OF THE BODY, e.g. STENTS; ORTHOPAEDIC, NURSING OR CONTRACEPTIVE DEVICES; FOMENTATION; TREATMENT OR PROTECTION OF EYES OR EARS; BANDAGES, DRESSINGS OR ABSORBENT PADS; FIRST-AID KITS
  • A61F2/00—Filters implantable into blood vessels; Prostheses, i.e. artificial substitutes or replacements for parts of the body; Appliances for connecting them with the body; Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
  • A61F2/82—Devices providing patency to, or preventing collapsing of, tubular structures of the body, e.g. stents
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61L—METHODS OR APPARATUS FOR STERILISING MATERIALS OR OBJECTS IN GENERAL; DISINFECTION, STERILISATION OR DEODORISATION OF AIR; CHEMICAL ASPECTS OF BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES; MATERIALS FOR BANDAGES, DRESSINGS, ABSORBENT PADS OR SURGICAL ARTICLES
  • A61L2420/00—Materials or methods for coatings medical devices
  • A61L2420/02—Methods for coating medical devices
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/90—Stent for heart valve
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10S623/00—Prosthesis, i.e. artificial body members, parts thereof, or aids and accessories therefor
  • Y10S623/901—Method of manufacturing prosthetic device
• • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
  • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
  • Y10T—TECHNICAL SUBJECTS COVERED BY FORMER US CLASSIFICATION
  • Y10T428/00—Stock material or miscellaneous articles
  • Y10T428/31504—Composite [nonstructural laminate]
  • Y10T428/31536—Including interfacial reaction product of adjacent layers

Definitions

• the invention relates to methods for coating stents, in particular cardiovascular implants with a polysaccharide layer or Polysaccharide derivative layer and manufactured by these processes Stents.
• polysaccharides as are known to be biocompatible. Typical representatives are in this context Heparin, chitosan, alginate or hyaluronic acid. The latter have on the one hand it has proven to be very well tolerated by the body, and on the other hand, coatings made of hyaluronic acid hydrophilic and consequently those provided with it Devices easy to implant.
• US-A-4,957,744 relates to cross-linked esters of hyaluronic acid which for various medical and cosmetic articles as well as pharmaceutical Compositions are used.
• the networked esters result from the esterification of polyhydric alcohols with two or more carboxy groups of hyaluronic acid.
• Such cross-linked esters are especially in the field of bioabsorbable plastics for medical and surgical items can be used.
• WO 8802623 A1 also relates to biomaterials biocompatible surface, taking a variety of starting materials and binding mechanisms including the use of hyaluronic acid for the production of a biocompatible contact lens is disclosed.
• the object of the present invention is therefore to provide a method for coating stents with a polysaccharide layer, which have an improved adhesion to the substrate surface of the Has the implant and is more functional in its provision Stents.
• the basic variants 1 and V of the method according to the invention provide the covalent attachment of the non-cross-linked polysaccharide for one significant increase in the adherence of the polysaccharide layer what is experimentally detectable.
• the further layer can be considered as not cross-linked Polysaccharide applied and then cross-linked or applied directly as cross-linked polysaccharide.
• a particularly suitable polysaccharide for use in the invention is the already mentioned hyaluronic acid, which can be applied to a wide variety of substrate surfaces of implants can.
• Alloplastic vascular wall supports - so-called “stents” - are usually coated with amorphous silicon carbide (a-SiC: H), which with Hyaluronic acid forms a particularly intimate and strong bond.
• a-SiC amorphous silicon carbide
• the method according to the invention is based on the coating of a Described substrate surface made of amorphous silicon carbide, for example on a stent with a basic structure made of a tantalum alloy is applied.
• Basic principles of the activation of the silicon carbide substrate surface are DE 195 33682 A1 of the applicant Removable, the attachment and immobilization of heparin on a Silicon carbide coating disclosed.
• the substrate surface is rinsed with water and incubated in a 20 ⁇ 10 -6 molar Fmoc-p-Bz-Phe-OH solution in N, N'-dimethylformamide (DMF).
• the Fmoc-p-Bz-Phe-OH solution which acts as a photoactive spacer substance, can be obtained as a commercially available product "Fmoc-p-Bz-Phe-OH", product number B 2220 from "Bachem Biochemica GmbH", Heidelberg.
• the reduction of the benzophenone is initiated by irradiation with UV light. After the UV irradiation, the reaction solution is poured off and the substrate surface is rinsed several times with distilled water.
• the next step involves splitting off the Fmoc protecting group 25% piperidine solution in DMF. On the now exposed and responsive Amino group binds the hyaluronic acid. This will be first non-cross-linked hyaluronic acid covalently to that treated Tied substrate surface. The polysaccharide layer thus formed can then be cross-linked.
• a silanized benzophenone in particular 4- (3'-chlorodimethylsilyl) propyloxybenzophenone
• an organic solvent such as toluene
• Et 3 N as a catalyst
• the substrates are rinsed in chloroform and then in methanol.
• the layer system substrate-spacer is then wetted with a 0.1% -2% aqueous hyaluronic acid solution and then dried.
• the hyaluronic acid is covalently bound to the present benzophenone under the action of UV radiation at a wavelength of 340 nm, which initiates the reduction of the benzophenone.
• the photochemical reaction can also be carried out in aqueous Hyaluronic acid solution can be performed.
• This photochemical reaction leads to a covalent bond between the benzophenone and a C-H group the polymer chain, especially hyaluronic acid. This to the Substrate surface covalently attached polysaccharide layer can then cross-linked.
• Chitosan can be incubated in a 0.2% Chitosan solution in a 1-2% acetic acid solution at 65 ° C for 1 h be bound.
• the stents are then deionized Rinsed water and then dried. This to the substrate surface covalently linked polysaccharide layer can then be cross-linked become.
• a covalently linked chitosan layer allows one achieve good detention.
• the glycosaminoglycan chitosan (Mw: 100,000 to 1,000,000 Daltons) is a chemical multi-stage reaction with the help of a spacer covalently to an amorphous silicon carbide layer (a-SiC: H), that covers the base body of the stent.
• a-SiC amorphous silicon carbide layer
• Fmoc-p-BZ-Phe-OH N- (9-Fmoc) -l- (4-benzoyl) -phenylalanine; 2 ml; 10 mmol / l; available from Bachem
• DMF N'-dimethylformamide
• the stent is then in a 0.2% solution of chitosan in 1% Acetic acid and N- (3-dimethylaminopropyl) -N'-ethylcarbodiimide hydrochloride (50 mg / ml) incubated in ice water for at least 12 hours.
• the covalent The chitosan is coupled by forming a peptide bond between the activated carboxylic acid of the spacer and the amino group of the Chitosans or formation of an ester bond between the activated Carboxylic acid of the spacer and the hydroxyl group of the chitosan.
• the sample is rinsed several times with deionized water and then dried.
• Adhesion promoter serves and for a subsequent covalent attachment of a Polysaccharide layer suitable functional groups on the surface having.
• Adhesion promoter layer can be Achieve plasma polymerization of N-heptylamine and acetaldehyde.
• the plasma polymerization takes place with a 40 kHz model plasma system Piko from Diener electronics.
• Precourser can acetaldehyde, amyl alcohol, allylamine, ethyl acetoacetate or Acrylic acid can be used.
• the plasma polymerized layers have due to their hydrophilicity, good wetting with hyaluronic acid solutions on. Furthermore, a thin one can be found on the functional surfaces Layer of hyaluronic acid or other polysaccharides with the help of Couple glutaraldehyde, epichlorohydrin, or carbodiimides.
• the recipient is flushed with oxygen to finally remove residual gas, with continuous evacuation.
• the sample room is kept for 10 min. rinsed and for the surface activation the plasma is ignited in the presence of a Teflon block.
• the power of the reactor is approx. 200 W and during the surface treatment there is an oxygen flow of approx. 40 cm 3 / min. maintained. Activation and simultaneous plasma cleaning takes 5-10 minutes.
• the power is increased to 80 W. regulated down and the Precourser is let into the recipient.
• the polymerization time is 5 minutes with the aerometer open.
• Deactivation can result in further surface activation with oxygen done, but then the power is only 80 W with a duration of approx. 30 sec This short surface activation leads to a further one improved wettability of the surfaces.
• the hyaluronic acid with the help of a water-soluble carbodiimide covalently to the complex substrate-adhesive layer tethered.
• the covalent connection of the Hyaluronic acid on the acetaldehyde plasma polymer takes place directly with the help a diimidazole or with a polyethyleneimine liner, which is applied by means of reductive amination.
• the covalent Linking of hyaluronic acid to this substrate-adhesion promoter complex takes place with the help of a water-soluble carbodiimide. This to the Adhesive layer covalently attached polysaccharide layer can then cross-linked.
• the substrate surface can by derivatized polyhydroxybutyric acid, which is an experimental proven good layer adhesion on silicon carbide and metals has to be functionalized.
• the functionalization of polyhydroxybutyric acid is carried out by amination.
• the covalent connection of the Hyaluronic acid to the amino group of the functionalized Polyhydroxybutyric acid (adhesion promoter layer) is made using a water soluble carbodiimide to form a peptide bond.
• a monolayer of chitosan can be created as follows:
• the pre-cleaned stent is dried at 75 ° C for 30 minutes in a drying oven.
• the still warm stent is then incubated for 10 minutes in a silane solution consisting of 3 ml of anhydrous toluene, 20 ⁇ l of 3- [2- (2-aminoethylamino) ethylamino] propyl-trimethoxysilane and 70 ⁇ l of Et 3 N at room temperature with repeated gentle shaking.
• the stents are then dried at 75 ° C. for 1 hour.
• the stent is then rinsed with toluene or chloroform and dried again.
• adipic acid via a solution of 10 mg / ml adipic acid in water to produce functional carbonyl functions on the surface of the implant.
• the adipic acid is previously activated in THF or DMF with a carbodiimide or diimidazole.
• the connection of chitosan follows. To do this, the implant is incubated in a 0.2% solution of chitosan in a 1-2% acetic acid solution at room temperature for 1-4 hours. This is followed by rinsing with deionized water and drying.
• Hyaluronic acid can be crosslinked with glutaraldehyde as follows:
• the implant is coated with a 0.1-2% hyaluronic acid solution and then exposed to a crosslinker solution for several hours.
• the crosslinker solution consists of 240 ml acetone, 80 ml glutaraldehyde in 25% solution in water and 1.6 ml HCL 3 M. Then the Crosslinker solution exchanged for a new solution and it will work again incubated at room temperature for several hours.
• the means Glutaraldehyde cross-linked hyaluronic acid is distilled several times Washed water. Then the sample is in a 0.5-3% strength Solution of the sodium cyanoborohydride for 1 hour at room temperature incubated.
• the fixer solution is withdrawn and several follow Wash steps in bidistilled water and isotonic saline.
• Crosslinking of hyaluronic acid with bifunctional aldehydes and Formaldehyde takes place in a process analogous to the crosslinking of hyaluronic acid with glutaraldehyde.
• 2 g hyaluronic acid are used to crosslink hyaluronic acid with divinyl sulfone in 50 ml of a 0.1 M aqueous NaOH solution to obtain a 2% solution dissolved.
• the solution is put on ice.
• 2 ml of divinyl sulfone are added.
• the emerging Two-phase mixture is stirred on ice for 15 min. After 5 minutes is only another phase to watch.
• the implants are in this solution dipped and then dried.
• crosslinking and covalent attachment of the hyaluronic acid is on Layer systems made of amorphous silicon carbide spacer and an amorphous one Silicon carbide spacer polysaccharide monolayer realizable with diimidazole.
• the implant with attached spacer or with a polysaccharide layer is immersed in an acetone solution containing diimidazole.
• the substrate-spacer complex or the polysaccharide layer is in the for at least 30 minutes Activated diimidazole-containing acetone solution and then in an aqueous Hyaluronic acid solution dipped or with a hyaluronic acid solution sprayed.
• the stent is 0.5-1 sec. sprayed at a carrier air pressure of 2-4 bar. Between the spraying steps the stent is 15-30 sec. dried with warm air supply.
• the OH and NHR groups of polysaccharides are crosslinked with With the help of acid dichlorides or phosphorus oxychloride with the formation of Ester or amide groups and with the release of HCL in the organic Solvent.
• a derivatization of the coated hyaluronic acid hydrogel on the The implant can also be implemented as follows.
• a polymer-analogous conversion of hyaluronic acid delays the enzymatic degradation of hyaluronic acid in vivo or stabilizes the hyaluronic acid in the body, as the following application example shows:
• the degree of sulfation in this polymer-analogous reaction can be varied by the amount of sulfating agent SO 3 * pyridine added, the reaction time and the reaction temperature.
• Drug loading with suitable pharmaceuticals usually takes place after Crosslinking and fixation of the polysaccharide layer in the swollen state.
• the active ingredient can be pre-sprayed or dipped the coating or during the coating with the polysaccharide respectively.
• the active ingredient is usually embedded in Diffusion processes.
• the active ingredient is immersed in a hyaluronic acid layer, such as it is available according to one of the preceding examples, embedded.
• the implant is placed in a solution of 15 mg cyclosporin per ml parity ethanol-water mixture immersed.
• the ratio of 1: 1 of ethanol to water has been chosen to carry out the Diffusion process proven to be surprisingly effective.
• Other Conditions, especially those with increased ethanol, slow them down Embedding The implant remains depending on the layer thickness and Degree of crosslinking of the polysaccharide layer for at least one hour in the Solution.
• the implant is then removed and dried. at a coating amount of 0.5 mg hyaluronic acid is on this Amount of cyclosporin that can be stored at least 0.2 mg.

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• Health & Medical Sciences (AREA)
• Heart & Thoracic Surgery (AREA)
• Surgery (AREA)
• Vascular Medicine (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Materials For Medical Uses (AREA)

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• 2002
  • 2002-05-24 DE DE2002123310 patent/DE10223310A1/de not_active Withdrawn
• 2003
  • 2003-05-13 EP EP20030090138 patent/EP1364664A1/fr not_active Withdrawn
  • 2003-05-14 AU AU2003240641A patent/AU2003240641A1/en not_active Abandoned
  • 2003-05-14 WO PCT/EP2003/005062 patent/WO2003099348A1/fr not_active Application Discontinuation
  • 2003-05-23 US US10/444,827 patent/US20040091605A1/en not_active Abandoned
• 2006
  • 2006-09-13 US US11/531,512 patent/US8173196B2/en not_active Expired - Fee Related

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